Lipid-dependent regulation of human Th17 cell function

人类 Th17 细胞功能的脂质依赖性调节

• 批准号: 9176733
• 负责人: Jun R. Huh
• 金额: $ 44.27万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9176733
• 关键词: Adverse effects; Arthritis; Autoimmune Diseases; Autoimmune Process; Biogenesis; CD4 Positive T Lymphocytes; Cell Differentiation process; Cell Lineage; Cell physiology; Cells; Chemicals; Colitis; Cytoplasm; Data; Development; Disease; Disease model; Effector Cell; Family; Fatty Acids; Fatty Liver; Gene Expression; Gene Targeting; Genes; Genetic Screening; Genetic screening method; Goals; Helper-Inducer T-Lymphocyte; Human; Immune; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Interleukin-17; Kinetics; Lead; Ligands; Light; Link; Lipids; Liver diseases; Memory; Metabolic; Metabolism; Modeling; Molecular; Multiple Sclerosis; Mus; Nonesterified Fatty Acids; Nuclear Hormone Receptors; Organelles; Orphan; PPAR gamma; Pathology; Pathway interactions; Physiological; Play; Polyunsaturated Fatty Acids; Production; Proteins; Psoriasis; Regulation; Regulatory T-Lymphocyte; Retinoids; Role; Specificity; Sterols; T cell differentiation; T-Lymphocyte; Testing; Triglycerides; abstracting; chemical genetics; cytokine; gain of function; knock-down; lipid metabolism; macromolecule; novel; novel therapeutics; programs; receptor; response; small hairpin RNA; small molecule; treatment strategy

Abstract Th17 cells are an Interleukin-17-producing subset of CD4+ T effector cells that are centrally implicated in many human inflammatory and autoimmune diseases, from inflammatory bowel disease to multiple sclerosis. The retinoid orphan receptor gamma t (RORγt), a nuclear hormone receptor, programs Th17 cell development and function. With the ultimate goal of modulating inflammatory T cells in disease settings, we undertook chemical and genetic screening to identify RORγt target genes that drive human Th17 cell function. Intriguingly, our results implicated a group of genes in a novel pathway that would link lipid metabolism, RORγt activity and Th17 cell functions. We will thus test the hypothesis that Th17 cell function is controlled in large part, by RORγt target genes, via lipid droplets (LDs) (cellular organelles associated with lipid metabolism). We will take the following approaches: First, we will determine if LD- related genes – specifically, HILPDA and BNIP3 – are necessary, sufficient and specific regulators of human Th17 cell functions. Second, we will elucidate the molecular mechanisms by which LDs modulate Th17 cell differentiation. Third, using autoimmune disease models in mice, we will determine the physiological significance of LDs in inflammation and autoimmune pathologies. Our results may shed a light on novel lipid-regulatory mechanisms that control Th17 cell responses in inflammatory diseases.

摘要 Th 17细胞是产生白细胞介素-17的CD 4 + T效应细胞亚群，其集中在 与许多人类炎症性和自身免疫性疾病有关， 多发性硬化症类维生素A孤儿受体γ t（RORγt），一种核激素 受体，程序Th 17细胞的发育和功能。最终目的是调节 在疾病环境中的炎性T细胞，我们进行了化学和遗传筛查， 鉴定驱动人Th 17细胞功能RORγt靶基因。有趣的是，我们的结果 提示一组基因参与了一种新的途径，该途径将脂质代谢、RORγt活性 Th 17细胞功能因此，我们将检验Th 17细胞功能在以下条件下受控制的假设： 很大一部分是通过RORγt靶基因，通过脂滴（LDs）（与RORγ t相关的细胞器）， 脂质代谢）。我们将采取以下方法：首先，我们将确定是否与LD相关 基因-特别是，HILPDA和BNIP 3-是必要的，足够的和特定的调节剂， 人Th 17细胞功能其次，我们将阐明LD的分子机制， 调节Th 17细胞分化。第三，使用小鼠自身免疫性疾病模型，我们将 确定LD在炎症和自身免疫病理学中的生理学意义。 我们的研究结果可能揭示新的脂质调控机制，控制Th 17细胞 炎症性疾病的反应。